Gastroeophageal Reflux Disease is reported in over 20% of the population. It is estimated that 7-10% of US population suffers daily from heartburn the cardinal symptom of GERD which negatively impacts the quality of life, work productivity and health care expenditure. While mucosal injury in GERD can be adequately treated with acid suppressive therapy, remedying the symptom of heartburn in the absence of mucosal injury which constitute over half of these patients such as those found in non-erosive reflux disease (NERD), functional heartburn (FH) and pain in non-cardiac chest pain (NCCP) poses a significant clinical challenge. This shortcoming is in part due to lack of a clear understanding of the cerebral cortical mechanism involved in sensory physiology and pathophysiology of reflux disease. The current proposal addresses this deficiency at two levels. At the cerebral cortical level in humans it utilizes advance imaging technology to characterize for the first time the effec of chronic and acute esophageal acid exposure on local and large scale cortical networks that are involved in visceral sensation, interoception/homeostasis and awareness in controls and patients with various GERD sub-types. We will examine the effects of age and gender, use functional connectivity alterations to classify subtypes of GERD patients, and will determine whether the effect of esophageal acid exposure on brain functional connectivity extends beyond sensory networks to include motor networks such as swallowing. The results of these studies can open new avenues to objectively diagnose subtypes of GERD and potentially other functional disorders At brain receptor levels in rats, this proposal uses an integrative neurobiological and electrophysiological approach to determine the effects of esophageal acid exposure on the neural plasticity of cerebral cortex at different stages of life. These studies promise to provide crucial new information about modulation of excitatory and inhibitory receptor sub-types by repeated esophageal acid exposure so badly needed to help guide identification of new therapeutic targets. We have assembled a multidisciplinary, interdepartmental team of investigators comprised of, Neurophysiologists, biophysicists, neurologists, molecular biologist and gastroenterologists to help execute the mandates of this clinical and translational proposal